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Biomedical subjects

M D Rawlins

Publications and source records attributed to M D Rawlins.

At least 55 records · Page 3Linked to original sources
PubMed1991

Study of United Kingdom product licence applications containing new active substances, 1987-9.

OBJECTIVES: To investigate the fate of product licence applications containing new active substances in relation to their degree of innovation and therapeutic category. To assess the numbers of volunteers and patients exposed to a new active substance when marketing autorisation is first sought. DESIGN AND SETTING: Observational study of records for each licence application submitted to the United Kingdom licensing authority for marketing authorisation from 1987 to 1989. SUBJECTS: 118 product licence applications containing one or more new active substances. MAIN OUTCOME MEASURES: Success of application for product licence as assessed by the decision of the Committee on Safety of Medicines to advise the granting of a licence (with or without conditions) or provisionally advise its refusal on the grounds of quality, safety, or efficacy. Assessment of numbers of volunteers and patients exposed to each substance during premarketing studies and clinical trials, and the numbers of treated patients available for an assessment of safety. RESULTS: 118 relevant product licence applications were submitted during the review. Although 60% (52/86) of semi-innovative products fell into one of three therapeutic categories (cardiovascular, central nervous system, or anti-infective agents), only 41% (13/32) of fully innovative products fell into these categories. 47 applications were granted (conditionally or unconditionally) but the success rate for fully innovative products (56%, 18/32) was greater than that for semi-innovative products (34%, 29/86). The number of volunteers and patients exposed to a new product at submission varied widely and tended to be greater for successful applications. CONCLUSION: The results suggest a broadening of the pharmaceutical industry's research and development programmes and that a more liberal licensing policy exists for fully innovative products than for semi-innovative products. The relatively limited exposure of patients to new active substances at licensing underlines the importance of rigorous postmarketing surveillance.

Consumer Product Safety↗
PubMed1991

The relationships between dose and concentration of tolbutamide and insulin and glucose responses in patients with non-insulin-dependent diabetes.

It is uncertain how the hypoglycaemic effect of sulphonylureas varies with drug concentration in patients with non-insulin-dependent diabetes mellitus. The inter-relationship of tolbutamide dosage and concentration, and glucose and insulin concentrations were therefore examined in 54 out-patients (the observational group) and in 20 patients studied under controlled conditions (the experimental group). In the observational group, tolbutamide concentration depended significantly on the daily dose, time from dose to sampling, body weight, and age. Blood glucose and insulin concentration were related, but were independent of tolbutamide concentration. In the experimental group, peak, but not pre-dose, tolbutamide concentration, depended on dose and on body mass index. Fasting and maximum post-prandial blood glucose concentration were positively correlated with maximum tolbutamide concentration, probably because tolbutamide dosage was highest in those with the poorest response. In the subset with a fasting blood glucose concentration of less than 8 mmol.l-1, neither glucose nor insulin concentrations depended significantly on tolbutamide concentrations. Tolbutamide concentration does not directly determine hypoglycaemic response in outpatients, and therapeutic monitoring of drug concentrations would not improve the management of such patients.

Aged↗
PubMed1991

A double-blind placebo controlled dose response study of noberastine on histamine induced weal and flare.

The antihistaminic effects of 7 days treatment with each of three doses of noberastine (10, 20 and 30 mg) were compared to placebo in 12 healthy male volunteers. The antihistaminic activity was assessed from the inhibition of weal and flare formation after intradermal histamine injections. For both weal and flare there was a highly significant effect of treatment with each of the three doses of noberastine, compared to placebo. The 30 mg daily dose produced the maximum inhibition of weal and flare. The daily mean values for the assessment of sedation by visual analogue scales at 09.00 h, 15.00 h and 21.00 h showed no significant treatment, or order, effect for any of the three doses of noberastine compared to placebo. The mean steady-state plasma concentrations of noberastine were significantly higher with increasing daily doses of noberastine (trough concentrations: 1.0, 1.6 and 2.2 ng.ml-1; peak concentrations: 3.5, 13.4 and 20.9 ng.ml-1 for 10, 20 and 30 mg daily dose, respectively). The percentage weal inhibition correlated (r = 0.77) with steady-state noberastine plasma trough levels. The percentage flare inhibition showed a weaker correlation (r = 0.35) with steady-state noberastine plasma trough levels.

Adult↗
PubMed1991

The biochemical and haemodynamic effects of adrenaline in lignocaine local anaesthetic solutions in patients having third molar surgery under general anaesthesia.

The effects of adrenaline-containing and adrenaline-free lignocaine local anaesthetic solutions injected in doses consistent with clinical practice on plasma potassium concentration, blood glucose levels and haemodynamic responses were investigated in 20 patients having third molar surgery under general anaesthesia. All patients received a standard general anaesthetic regime. Ten patients were given 4.0 ml of 2% lignocaine as an inferior dental and long buccal block during their general anaesthetic and the other 10 received 4.0 ml of 2% lignocaine containing 1:80000 adrenaline in the same manner. There were no significant differences between treatments in blood pressure or heart rate. However, there were significant differences between treatments in plasma potassium concentration and blood glucose levels.

Adult↗
PubMed1991

Metabolism of aldrin to dieldrin by rat skin following topical application.

Metabolism of the pesticide aldrin to dieldrin in the rat was studied following topical and ip administration of 0.1-10 mg aldrin/kg body weight. When aldrin was applied topically to the dorsal skin at a dose of 10 mg/kg body weight, absorption was less efficient than after ip administration; lower blood levels of aldrin and dieldrin were seen and peak dieldrin levels were delayed. After ip administration of 1 or 10 mg aldrin/kg body weight, dieldrin was found at similar concentrations in the dorsal and ventral skin 7 hr later, whereas 7 hr after topical administration of 10 mg aldrin/kg, the dieldrin concentration in the skin at the dorsal site of application was four times higher than that at a ventral skin site. Similar differences in dieldrin concentrations between dorsal and ventral skin persisted throughout the 7-hr period following topical application. The results indicate that topically applied aldrin is metabolized to dieldrin in the skin during absorption, but the overall proportion of metabolism that takes place in the skin is small compared with the contribution of the liver. Dieldrin was not detected in the ventral skin remote from the application site 1 hr after topical application of aldrin, whereas a dieldrin concentration of 2.2 nmol/g was detected in the skin of the application site at this time; more than 99% of this dieldrin was probably formed locally by dermal metabolism of percutaneously absorbed aldrin. The efficiency of conversion of applied aldrin to dieldrin decreased with increasing aldrin dose in the range 0.1 to 10 mg/kg.

Administration, Topical↗
PubMed1991

The effects of enalapril and sulindac on the dermal response to substance P and neurokinin A.

The effects of pretreatment with enalapril, and sulindac, on the weal response to intradermal injections of substance P and neurokinin A were assessed in a randomised, double-blind, placebo-controlled study. Weal responses to both substance P and neurokinin A depended significantly on dose. Neither enalapril nor sulindac, nor the combination of these agents influenced the responses to either tachykinin. These results do not suggest any role for substance P or neurokinin A in the clinical effects of angiotensin converting enzyme inhibitors.

Adult↗
PubMed1991

Geographical differences in adverse drug reaction reporting rates in the Northern Region.

The reporting rates of adverse drug reactions in the Northern Region have been examined with respect to source (hospital or general practice) and district of origin for the 3 years 1986-88. Mean annual reporting rates, corrected for population, or clinical activity, varied approximately 4-fold in general practice (0.066 to 0.257 reports per 1000 resident population) and more than 12-fold in hospitals (0.14 to 1.77 reports per 1000 deaths and discharges). There was no correlation between hospital and general practice reporting rates in the same health district. Overall more reports were received from general practice (1606) than hospitals (1000), although proportionally more reports of serious adverse reactions originated from hospitals. The reasons for these differences are unclear.

Drug-Related Side Effects and Adverse Reactions↗
PubMed1991

Hospital prescribing and usage of hypnotics and anxiolytics.

In-patient prescribing and usage of hypnotic and anxiolytic drugs were surveyed in a teaching hospital for 4 to 6 weeks. Twenty-one percent of admissions were prescribed these drugs which were predominantly benzodiazepines. Few patients (1.6%) were discharged with such prescriptions and subsequent usage in the community was similar to that before admission to hospital (6.1% and 6.4% respectively). In-patient consumption increased with patient age and both prescriptions and consumption were greater in women than men.

Anti-Anxiety Agents↗
PubMed1991

Lack of effect of flosequinan on the pharmacokinetics of theophylline.

The pharmacokinetics of theophylline (240 mg) p.o. were studied before and after the administration of oral flosequinan for 14 days in 21 healthy volunteers using a randomised cross-over design. Comparisons of Cmax, tmax, AUC, CL of theophylline and urinary recovery of the parent drug and metabolites showed that flosequinan had no significant effect on the disposition of theophylline.

Administration, Oral↗
PubMed1991

Clinical pharmacology of prochlorperazine in healthy young males.

1. The pharmacokinetics and pharmacodynamics of prochlorperazine (PCZ) have been studied in healthy young males following single 12.5 mg i.v. and 50 mg oral doses, and during repeated doses (25 mg twice daily) for 14 days. 2. Oral bioavailability was low and an N-desmethyl metabolite was detected. Plasma clearance was high (0.98 1 kg-1 h) and the volume of distribution was large (12.9 1 kg-1) after i.v. dosing. 3. The terminal elimination half-life of PCZ was 9 +/- 1 h and 8 +/- 2 h after i.v. and single oral dosing, respectively. The urinary recoveries of drug and metabolite were low. 4. Accumulation of PCZ and its metabolite occurred following repeated dosing. The half-life at the end of 14 days therapy was 18 +/- 4 h. 5. Postural tachycardia, decreased salivary flow, impaired psychomotor function and a diminished level of arousal were observed after intravenous PCZ. Similar effects, but of lower magnitude were observed after single oral doses. During chronic dosing postural tachycardia and antihistaminic effects were observed, the latter not being observed after single doses. 6. After single intravenous dosing the maximal drug effects occurred 2-4 h after peak plasma drug concentrations for all measures except for plasma prolactin and self-scored restlessness 7. An antagonist action at dopamine (D2), muscarinic-cholinergic and alpha-adrenoceptors is postulated after single doses, with antihistaminic effects during chronic dosing, possibly indicating the presence of an active metabolite.

Administration, Oral↗
PubMed1990

The metabolic effects of aspirin in fasting and fed subjects: relevance to the aetiology of Reye's syndrome.

As a possible model for the mechanism of precipitation of Reye's Syndrome in children the metabolic effects of oral aspirin were studied in normal subjects in the fasted and fed states, to determine whether aspirin altered fatty acid oxidation. Starvation increased blood 3-hydroxybutyrate concentrations, but aspirin had no effect on this or other metabolite concentrations in either the fasted or fed states.

3-Hydroxybutyric Acid↗
PubMed1990

The association of age and frailty with paracetamol conjugation in man.

The association of age, physical frailty and liver size upon hepatic conjugation reactions was studied using paracetamol as a model drug. Nineteen fit subjects (mean age 26 years), 20 fit subjects (mean age 73 years), and eight frail, hospitalized subjects (mean age 82 years) were recruited. Paracetamol clearance expressed in terms of body weight was significantly lower in the fit elderly than in the fit young subjects, and was lowest in the frail elderly subjects (p less than 0.01). There was no difference in paracetamol clearance expressed per unit volume of liver between the fit young and fit elderly subjects but it was significantly reduced in the frail subjects. Although the partial metabolic clearance to paracetamol sulphate was preserved per unit volume of liver with ageing and frailty, the partial metabolic clearance to paracetamol glucuronide per unit volume of liver was markedly reduced in the frail elderly (p less than 0.01) when compared with the fit subjects. These results show that age-associated changes in paracetamol clearance are attributable to both changes in liver volume and in general health. The findings underline the important influences of the elderly person's physical state upon drug clearance.

Acetaminophen↗
PubMed1990

The effect of sulindac on dermal responses to bradykinin in normal subjects given an angiotensin converting enzyme inhibitor.

The ability of sulindac to modify the weal response to four doses of intradermal bradykinin in subjects given enalapril was tested in a double-blind cross-over study in normal volunteers. The dose-dependent increase in skin thickness after bradykinin was significantly reduced by prior administration of sulindac. Certain of the actions and adverse effects of angiotensin converting enzyme inhibitors may be due to the interaction of prostaglandins and bradykinin.

Adult↗
PubMed1990

Hepatic drug clearance: the effect of age using indocyanine green as a model compound.

The hepatic extraction ratio and clearance of indocyanine green (ICG) were determined and used to derive apparent liver blood flow in nine subjects between the ages of 22 and 83 years. There was no correlation between the hepatic extraction ratio of ICG and age (rs = -0.435, NS). There was a significant negative correlation between both ICG clearance and age (rs = -0.710, P less than 0.05) and apparent liver blood flow and age (rs = -0.750, P less than 0.05). These results validate the comparison of liver blood flow values derived from ICG clearance in humans over a wide age range and confirm that liver blood flow does fall with age.

Adult↗
PubMed1990

Lack of effect of co-trimoxazole on the pharmacokinetics and pharmacodynamics of nifedipine.

The pharmacokinetics of nifedipine and its primary oxidised metabolite, M-I were studied in nine healthy volunteers following a single oral dose of 20 mg nifedipine alone or after pretreatment with oral co-trimoxazole. Following pretreatment with co-trimoxazole, no significant effect was detected on maximum plasma concentration, elimination half-life, or area under the plasma concentration-time curve of either nifedipine or M-I, nor on the blood pressure response to nifedipine.

Adult↗